Abstract It has become evident that the microvasculature (i.e., microscopically small blood vessels) plays a critical role in the plasticity of the brain for fundamental processes: (i) neurogenesis, (ii) migration of neuronal precursors to their final destination in the brain, (iii) axonal, dendritic and synaptic plasticity during brain development, learning, aging and neurodegeneration, and (iv) recovery from traumatic brain injury and brain inflammation. For more than thirty years, investigators have attempted to trace, reconstruct, visualize and quantitatively characterize the three-dimensional (3D) morphology of the brain's microvasculature in normal and pathological tissue (3D microangioarchitectonics). Yet, 3D microangioarchitectonics is rarely used in neuroscience research due to the paucity of adequate tools. The investigators who have started to study 3D microangioarchitectonics use software tools that were developed for other purposes. Because these software tools make use of data models which are inappropriate for 3D microangioarchitectonics and have not been validated against a manually established ground truth, the results must be considered faulty and irreproducible. To remedy this untenable situation we propose to create Vesselucida, an innovative software product to perform advanced, accurate and reproducible automatic 3D microangioarchitectonics in normal and pathological brain tissue. This software will allow significant advancements in (i) neuroscience research that addresses the roles of microvessels on various aspects of neuroplasticity, and (ii) pharmacological and biotechnology research and development. These advancements will be the basis for the development of innovative treatments to fight complex brain diseases. During Phase I we successfully established proof of concept and demonstrated that the development of Vesselucida represents substantial progress beyond the state-of-the-art, with great benefits for the neuroscience research community and society in general.